Feasibility and oncological safety of sentinel node biopsy in breast cancer patients with a local recurrence.

OBJECTIVES: To investigate the role and feasibility of sentinel lymph node biopsy (SLNB) in breast cancer patients with a local recurrence and no clinically positive axillary lymph nodes. MATERIALS AND METHODS: A total of 71 patients underwent SLNB for breast cancer recurrence. At first surgery, they had received SLNB (46.5%), axillary lymph node dissection (ALND) (36.6%) or no axillary surgery (16.9%). RESULTS: Lymphatic migration was successful in 53 out of 71 patients (74.6%) and was significantly higher in patients with previous SLNB or no axillary surgery than in those with previous ALND (87.9% vs. 53.8%; p = 0.009). Aberrant lymphatic migration pathways were observed in 7 patients (13.2%). The surgical SLNB was successfully performed in 51 patients (71.8%). In 46 patients (90.2%) the SLN was histologically negative, in 3 patients (5.9%) micrometastastatic and in 2 patients (3.9%) macrometastatic. The 2 patients with a macrometastates in SLN underwent ALND, In 4 out of the 18 patients with failure of tracer migration ALND, performed as surgeon's choice, did not find any metastatic node. After a median follow-up period of 39 months (range: 2-182 months), no axillary recurrence has been diagnosed. CONCLUSION: A SLNB in patients with locally recurrent breast cancer, no previous ALND and negative axillary lymph nodes is technically feasible and impacts on the ALND rate. In patients who at primary surgery received ALND, migration rate is significantly lower, aberrant migration is frequent and no clinically useful information has been obtained.

Duloxetine and escitalopram for hot flushes: efficacy and compliance in breast cancer survivors.

Selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) might be an effective treatment for hot flushes (HFs) in breast cancer survivors (BCSs). This study aims to compare the efficacy and tolerability of duloxetine (SNRI) versus escitalopram (SSRI) in reducing frequency and severity of HFs in BCSs and to assess the effect on depression. Thirty-four symptomatic BCSs with emotional impairment received randomly duloxetine 60 mg daily or escitalopram 20 mg daily for 12 weeks. Patients were asked to record in a diary HF frequency and severity at baseline and after 4 and 12 weeks of treatment. Depression was evaluated through validated questionnaires (Beck Depression Inventory and Montgomery Asberg Depression Rating Scale) at baseline and after 4 and 12 weeks of treatment. Both drugs showed a significant reduction of HF frequency and severity after 12 weeks of treatment with no significant difference between the two groups. A significant improvement in depression symptoms was observed at the end of the study period within both the groups, without difference between the two drugs. In conclusion, escitalopram and duloxetine are both effective treatment for the relief of HFs in BCSs, with similar beneficial effect. A significant improvement of depression was obtained with no major side effects.

Clinical-pathologic features, long term-outcome and surgical treatment in a large series of patients with invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC).

PURPOSE OF THE STUDY: A retrospective analysis on 1407 patients with invasive ductal carcinoma (IDC) and 243 invasive lobular carcinoma (ILC) was performed in order to compare the histological features, the immunohistochemical characteristics, the surgical treatment and the clinical outcome in the two groups. RESULTS: ILC seems to be more likely multifocal, estrogen receptor positive, HER-2 negative and to have a lower proliferative index compared to IDC. ILC, when treated with conservative surgery, required more frequently re-excision and/or mastectomy because of positive resection margins. No difference was observed in terms of 5-year disease free survival and local relapse free survival between the two groups, in the whole series and in the subgroup of patients treated with breast-conserving treatment. CONCLUSION: ILC can be safely treated with conservative surgery but a more accurate preoperative evaluation of tumor size and multifocality could be advocated, in order to reduce the re-excision rate.

Toxicological properties of nanoparticles of organic compounds (NOC) from flames and vehicle exhausts.

We examined the biological reactivity in vitro of nanoparticles of organic compounds (NOC) with diameters, d = 1-3 nm, a class of combustion-generated particulate relatively unstudied compared to larger more graphitic soot particles because of their small size even though they may contribute significantly to the organic fraction of PM sampled from vehicle exhausts and urban atmospheres. We tested NOC samples collected from 2004 model vehicle emissions and laboratory flames. NOC produced a dose dependent mutagenic response in Salmonella bacteria, suggesting that NOC may add significantly to the overall mutagenicity of vehicle emissions. Incubation with peptides caused agglomeration and precipitate of the otherwise stable NOC suspension, but the chemical and/or physical nature of the NOC-peptide interactions could not be resolved. A significant cytotoxic response was measured above a critical dose of NOC in mouse embryo fibroblasts NIH3T3 cells along with possible evidence of cellular uptake by optical and confocal microscopy. The toxicological assays showed that NOC collected from flames and vehicle exhausts effectively interacted in vitro with both prokaryotic and eukaryotic cells. Differences in mutagenic potencies observed for various Salmonella strains with and without metabolic activation indicate differences in the chemical composition of NOC collected from different vehicles and flames.

[Combustion generated nanoparticles: mutagenicity and chemical reactivity]. / Nanoparticelle generate dalla combustione: mutagenicità e reattività.

Nanoparticles of organic carbon (NOC) are formed in combustion of hydrocarbon-rich fuels and have been detected in vehicle exhausts, suggesting their presence in urban atmospheres. Epidemiological studies showed that some causal relationships exist between particle concentration in the air and a wide range of health effects, but no toxicological studies are reported on the potential health risk of particles smaller than 4 nm. The present study investigated the mutagenicity and the reactivity of NOC collected in water samples from the exhausts of diesel and gasoline engines. Mutagenicity was tested following the Ames Test, with and without metabolic activation. Reactivity was investigated by using a new approach aimed to identify electrophilic agents present in the sample material, which if introduced into the organism, could interact with nucleophilic sites of biological macromolecules (DNA and proteins), forming adducts. Given the large number of nucleophilc sites within biological macromolecules, the complexity of NOC, and the inexact knowledge of its chemical structure, this approach was simplified by examining in vitro interactions between NOC particles and model peptides through LCIMS analyses of incubation mixtures The results indicate a high reactivity and, in several cases, the mutagenicity of NOCs, thus calling for suitable biomarkers assess NOC exposure associated with vehicle emissions.

The influence of hormone replacement therapy on the pathology of breast cancer.

AIM OF THE STUDY: To assess whether the pathological characteristics of breast carcinomas arising in post-menopausal women who ever used hormonal replacement therapy (HRT) differ from those of post-menopausal patients who never used HRT. MATERIALS AND METHODS: Six hundred and forty three consecutive breast cancer patients were entered in a case control-study. Cases were represented by 111 breast cancer patients who had used or were using HRT at the time of diagnosis, while the remaining 532 patients who never used HRT were chosen as controls. RESULTS: Tumour diameter was smaller in HRT users (17.6 vs 22.1 mm; p=0.002) and tumours of lobular histology were almost twice more frequent among HRT users as in 'never users' (21 vs 12%; p=0.01). No differences were found in grading, hormonal receptor status and axillary nodal status. The expression of c-erb B-2, p53, Ki67 and PS2 measured by immunohistochemistry was similar in the two groups. CONCLUSIONS: Our findings suggest that HRT use may modify the pathological presentation of breast cancer. Further studies are indicated, while other clinical-pathological characteristics did not differ according to HRT use.

Detection of combustion formed nanoparticles.

UV-visible extinction and scattering and two extra situ sampling techniques: atomic force microscopy (AFM) and differential mobility analysis (DMA) are used to follow the evolution of the particles formed in flames. These particle sizing techniques were chosen because of their sensitivity to detect inception particles, which have diameters, d<5 nm, too small to be observed with typical particle measurement instrumentation. The size of the particles determined by AFM and DMA compares well with the size determined by in situ optical measurements, indicating that the interpretation of the UV-visible optical signal is quite good, and strongly showing the presence of d=2-4 nm particles. UV-visible extinction measurements are also used to determine the concentration of d=2-4 nm particles at the exhausts of practical combustion systems. A numerical model, able to reproduce the experimentally observed low coagulation rate of nanoparticles with respect to soot particles, is used to investigate the operating conditions in the combustion chamber and exhaust system for which 2-4 nm particles survive the exhaust or grow to larger sizes. Combustion generated nanoparticles are suspected to affect human and environmental health because of their affinity for water, small size, low rate of coagulation, and large surface area/weight ratio. The ability to isolate nanoparticles from soot particles in hydrosols collected from combustion may be useful for future analysis by a variety of techniques and toxicological assays.

UV-visible spectroscopy of organic carbon particulate sampled from ethylene/air flames.

A systematic comparison of spectra obtained with extra and in situ diagnostics in the soot preinception region of rich, premixed ethylene air flames suggests that combustion generated organic carbon (OC) particulate can be extracted from flames and isolated from other flame material for further chemical analysis. Both the trend with height above the burner and the form of UV fluorescence and absorption spectra from extra situ sampled material captured in water agree with those measured in situ. These results show that the OC particulate formed in flames is partially water soluble. However, the collection efficiency can be increased using less polar solvents, like acetonitrile and dichloromethane. The fluorescence spectra from the water samples are comprised both a naphthalene-like component and a broad band UV fluorescence component similar to that observed in situ which is attributed to flame generated OC particulate. The broad band UV fluorescence centered around 320 nm is also observed very early in flames and does not change considerably with increasing flame residence time. These results support previous hypotheses that the UV broad band fluorescence is from carbonaceous material comprised two-ring aromatics, formed earlier than soot in the flame, and is still present along with soot at higher heights or flame residence times.

How to manage the menopause following therapy for breast cancer. is raloxifene a safe alternative?

Raloxifene is a selective oestrogen receptor modulator (SERM) that has anti-oestrogenic effects on breast and endometrial tissue and oestrogenic actions on bone, lipid metabolism and blood clotting. In postmenopausal women raloxifene decreases bone turnover and increases bone mineral density, reducing the incidence of vertebral fractures. Unlike tamoxifen, raloxifene does not cause endometrial hyperplasia or cancer, as demonstrated by endometrial monitoring with ultrasonography and biopsy during treatment. Evidence suggests that raloxifene lowers total low-density lipoprotein cholesterol levels behaving like oestrogens, but does not increase high-density lipoprotein cholesterol levels. In randomised clinical trials on postmenopausal women with osteoporosis, raloxifene reduced the risk of newly diagnosed ER-positive invasive breast cancer by 76% during a median of 40 months of treatment. However, raloxifene does not alleviate early menopausal symptoms, such as hot flushes and urogenital atrophy, and may even exacerbate some of them. In conclusion, raloxifene may be an alternative for the prevention of long-term effects of oestrogen deficiency (osteoporosis and heart diseases) in women with previous breast cancer not having hot flushes. For symptomatic patients, the association of raloxifene with different drugs which have demonstrated efficacy in the control of vasomotor symptoms is now under evaluation.

HRT, breast and endometrial cancers: strategies and intervention options.

The demand for hormone replacement therapy (HRT) by women who enter the menopause is rapidly increasing in all developed countries. The concern that HRT may enhance morbidity and mortality from malignant diseases still limits the widespread adoption of hormonal treatments. Overall, epidemiological data on cancer incidence and HRT are reassuring, although long-term or inappropriate therapies may slightly increase the risk of developing malignant diseases. Many commercial hormonal compounds are currently available and the safest HRT regimen with regard to cancer risk must be identified. It is equally important that the best strategies for breast and endometrial surveillance in women commencing HRT be outlined, bearing in mind that the diffusion of hormonal therapies may be halted by unnecessary medical interventions.

Prostate specific antigen molecular forms in breast cyst fluid and serum of women with fibrocystic breast disease.

We have analyzed matched serum and breast cyst fluid samples for total PSA from 148 patients with fibrocystic breast disease. We have also determined the molecular forms of PSA (free PSA and PSA bound to alpha1-antichymotrypsin) in 78 breast cyst fluid samples. We found that total PSA can be detected in all cyst fluids and in about 75% of female sera. The median total PSA concentration in breast cyst fluid (bcf) is about 30 times higher than the median in the corresponding sera. Breast cyst fluid and serum PSA are not correlated with each other. Total serum PSA is inversely associated with patient age but the inverse association between bcf PSA and age is weak. Lower total PSA in bcf was seen in women who breast feed, and higher bcf PSA is associated with multiple cysts. Type I cysts (with a high K+/ Na+ ratio) tend to have higher total PSA than Type II cysts. All but three of the fractionated cyst fluids (75/78; 96%) had free PSA as the predominant molecular form. The most consistent finding of our study was the positive association between the cyst fluid K+/Na+ ratio and the free to bound PSA ratio. This association was confirmed by Spearman correlation as well as by Wilcoxon and chi-square analysis. Secretory/apocrine cysts (Type I) tend to have more total PSA and proportionally more free PSA than transudative/flattened cysts (Type II).

Quantification of pepsinogen C and prostaglandin D synthase in breast cyst fluid and their potential utility for cyst type classification.

OBJECTIVE: To quantify pepsinogen C (PEPC) and prostaglandin D synthase (PGDS) in breast cyst fluid and examine if these two parameters can be used for breast cyst type classification. DESIGN AND METHODS: We quantified PEPC and PGDS in 92 and 50 breast cyst fluids, respectively, using previously established immunofluorometric procedures. We then examined if the levels of PEPC or PGDS correlate with the type of cyst or with other clinicopathological variables. RESULTS: Quantitative analysis of the breast cyst fluids indicated that PEPC is present in all cyst fluids at various concentrations ranging from 3 to 31,000 ng/mL. PGDS positivity was confined to 30% of the cyst fluids. PEPC and PGDS levels were correlated with the breast cyst fluid cation ratio and were associated with the type of the cyst. Increased PEPC levels in breast cyst fluids were significantly correlated with a > or = 1.5 K+/Na+ ratio and were associated with the secretory/apocrine type of cyst (Type I) (p = 0.011). Immunoreactive PGDS levels were highly correlated with a low cation ratio and were associated with the transudative/flattened type of breast cyst (Type II) (p = 0.0003). A weak association was observed between PEPC levels in breast cyst fluid and menopausal status (p = 0.093). No significant associations were observed for either PEPC or PGDS concentration in breast cyst fluid and number of cysts, recurrence of the disease, family history of breast cancer, number of children, abortion, and breast feeding. CONCLUSIONS: Quantification of PEPC and PGDS in breast cyst fluid may be useful in the subclassification of cyst type in patients with gross cystic disease.

Ammonia detection and monitoring with photofragmentation fluorescence.

Excimer laser fragmentation-fluorescence spectroscopy is an effective detection strategy for NH(3) in combustion exhausts at atmospheric pressure and high temperatures. Two-photon photofragmentation of NH(3) with 193-nm light yields emission from the NH(A-X) band at 336 nm. There are no major interferences in this spectral region, and the sensitivity is at the parts per billion (ppb) level. Quenching of the NH(A) state radical by the major combustion products is measured and does not limit the applicability of the detection method. Detection limits in practical situations are of the order of 100 ppb for a 100-shot (1-s) average. This technique could prove useful in monitoring ammonia emissions from catalytic and noncatalytic NO(x) reduction processes involving ammonia injection.

Molecular forms of prostate-specific antigen in the serum of women with benign and malignant breast diseases.

Using a highly sensitive immunofluorometric procedure, we measured the total prostate-specific antigen (PSA) concentration in 632 sera obtained from female blood donors and women with idiopathic hirsutism, breast cancer or benign breast diseases. A total of 50 sera with total PSA > 15 ng l(-1) were fractionated by high-performance liquid chromatography (HPLC) in order to resolve the two immunoreactive molecular forms, i.e. free PSA (approximately 30 kDa) and PSA bound to alpha1-antichymotrypsin (PSA-ACT, 100 kDa). We found that breast cancer patients have presurgical serum total PSA levels similar to those of blood donors. Total serum PSA concentration decreases with age in women with idiopathic hirsutism, in cancer patients and in patients with benign breast diseases. The major molecular form of PSA in the serum of all normal and hirsute women (n = 15) is PSA bound to the proteinase inhibitor alpha1-antichymotrypsin. The major molecular form in 44% of presurgical cancer patient sera is free PSA. A total of 58% of benign breast disease patients also have in their serum mainly free PSA. We conclude that about half the patients with breast cancer or benign breast diseases have free PSA as the major molecular form in their serum, whereas patients without breast pathologies (normal blood donors, idiopathic hirsutism) have PSA bound to alpha1-antichymotrypsin as the major molecular form. The ratio of PSA/PSA-ACT may have value as a simple biochemical test for diagnosis of breast pathologies including breast cancer.

Clinical and ethical issues in the diagnosis of hereditary breast cancer (review).

A small subset of breast and ovarian cancers is related to the mutation of dominant susceptibility genes. The recent isolation of BRCA1 and BRCA2 has created great interest and expectations among members of families with a positive history for breast/ovarian cancer. We reviewed the literature to explore the clinical implications of genetic testing for BRCA1 and BRCA2 mutations among high risk women. Both the value of the information provided by the test and the efficacy of the preventive and diagnostic measures presently available have been examined. We also specifically address the issue of ethical dilemmas arising from widespread availability of genetic information, including psycological reactions of those who receive the test, genetic discrimination by health insurance companies or employers and prenatal testing for BRCA1 mutations.

TPS and CA 15.3 serum values as a guide for treating and monitoring breast cancer patients.

BACKGROUND: Tissue Polypeptide-specific Antigen (TPS) and CA 15.3 are two of the most widely studied tumor markers in the serum of breast cancer patients. TPS is a tumor associated proliferative marker which belongs to the cytoskeleton. CA 15.3 is a high molecular weight glycoprotein of clinical relevance in the monitoring of treatment and the detection of recurrence in breast cancer patients. PATIENTS AND METHODS: Serum values of TPS and CA 15.3 were measured in a prospective series of patients with primary breast cancer (n=267) and benign breast disease (n=46). The cut-off levels (95% specificity) determined for each test were 80 U/I for TPS and 30 k/U/l for CA 15.3. RESULTS: The diagnostic sensitivity was 0.31 for TPS and 0.32 for CA 15.3 for the detection of breast cancer. Serum TPS levels in breast cancer patients showed a relatively low positivity rate (33%), which was comparable with that of CA 15.3. Higher concentrations of TPS were found in cases with locally more advanced disease as well as in G3 tumors. By contrast, CA 15.3 basal levels were solely related to tumor size and nodal involvement. TPS and CA 15.3 levels were not related to estrogen and progesterone receptor status, peritumoral vessel invasion, multifocality and the in situ component of the tumor. After primary treatment, 20 patients developed distant metastases. In metastatic breast cancer patients TPS was more frequently and more markedly elevated than CA 15.3. In progressive disease, elevated values of TPS and CA 15.3 were found in 85% and 50%, respectively. The mean lead time was 10 months for TPS and 14 months for CA 15.3. Increasing values of TPS were independent of the site of metastasis, whereas elevated levels of CA 15.3 were mainly related to visceral metastasis. Local recurrences were usually associated with low levels of TPS and CA 15.3. By contrast, elevated values of TPS in locally recurred cases indicated rapidly progressive disease. CONCLUSIONS: Our study indicates that TPS and CA 15.3 are not helpful in distinguishing patients with breast cancer from patients with benign breast lesions. Nevertheless, at the time of diagnosis increased serum levels of the markers may facilitate the selection of high risk patients for whom additional treatment and careful follow up studies should be undertaken. Furthermore, TPS seems to be a reliable tumor marker for the early diagnosis of metastatic breast carcinoma independent of the site of metastasis, while increasing values of CA 15.3 are mainly related to visceral involvement.

Metabolic effects of tamoxifen in postmenopause.

Tamoxifen is actually considered the drug of choice for the hormonal treatment of early and metastatic breast cancer due to its efficacy and low toxicity. In addition, clinical trials of adjuvant therapy have demonstrated a 35% decrease in controlateral breast cancer in women receiving tamoxifen compared with controls, suggesting a potential role for this drug in chemoprevention of breast cancer in healthy women at increased risk of disease. Although tamoxifen is usually classified as an estrogen antagonist it also has partial estrogenic effects in some tissues such as liver, bone and uterus. The estrogenic action of tamoxifen on lipid metabolism and bone mineral density suggests additional benefits in protection against cardiovascular diseases and osteoporosis in postmenopausal women. Of particular interest could be the use of tamoxifen as an alternative to traditional estrogen replacement therapy in postmenopausal women previously treated for breast cancer or at increased risk of disease due to family history or histology on breast biopsy. The potential adverse effects of tamoxifen are partially similar to those of ERT and includes an increased risk of endometrial cancer, hepatic diseases, thromboembolic alterations and ocular toxicity. The mechanism of action of tamoxifen is briefly examined and the potential toxic effects and benefits of tamoxifen treatment are discussed.